Department of Pharmacology, Kyungpook National University School of Medicine, 101 Dongin-2-Ga, Daegu, 700-422 Republic of Korea.
Hypertension. 2012 Mar;59(3):621-6. doi: 10.1161/HYPERTENSIONAHA.111.182428. Epub 2012 Feb 6.
The renin-angiotensin system has been implicated in the development of hypertension and damages several organs. The expressions of the components of a local renin-angiotensin system (RAS) in the hypertensive rats differ from those of the normotensive rats. We hypothesized that local tissue-specific upregulation of angiotensin-converting enzyme 1 (ACE1) in hypertension is caused by epigenetic changes. Adrenal gland, aorta, heart, kidney, liver, and lung tissues were excised from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Ace1 mRNA and protein expressions were measured by real-time PCR and Western blot, respectively. Promoter methylation was revealed by bisulfite sequencing. Histone modifications, such as histone 3 acetylation (H3Ac), fourth lysine trimethylation (H3K4me3), and ninth lysine dimethylation (H3K9me2), were quantified by chromatin immunoprecipitation (ChIP), followed by real-time PCR. The expressions and associations of chromatin remodeling genes were analyzed by real-time PCR and ChIP, respectively. Local tissues from SHRs showed higher expressions of Ace1 mRNA and protein than those from the WKY rats. Ace1 promoter was mostly unmethylated in all of the tissues from both strains. The Ace1 promoter regions of SHR tissues were more enriched with H3Ac and H3K4me3, except in the lungs. The adrenal glands, hearts, and kidneys of SHRs showed less enrichment with H3K9me2. Valsartan treatment in SHRs decreased local Ace1 mRNA and protein expressions, which were accompanied by higher H3K9me2, as well as less H3Ac and H3K4me3. In conclusion, ACE1 is upregulated in local tissues of SHRs via histone code modifications.
肾素-血管紧张素系统（renin-angiotensin system）与高血压的发生和多个器官损伤有关。高血压大鼠局部肾素-血管紧张素系统（renin-angiotensin system，RAS）组成成分的表达与正常血压大鼠不同。我们假设高血压时局部组织 ACE1 的表达上调是由表观遗传变化引起的。从正常血压的 Wistar-Kyoto（WKY）大鼠和自发性高血压大鼠（spontaneously hypertensive rats，SHR）中切除肾上腺、主动脉、心脏、肾脏、肝脏和肺组织。通过实时 PCR 和 Western blot 分别测量 Ace1 mRNA 和蛋白表达。通过亚硫酸氢盐测序揭示启动子甲基化。通过染色质免疫沉淀（chromatin immunoprecipitation，ChIP）定量组蛋白修饰，如组蛋白 3 乙酰化（histone 3 acetylation，H3Ac）、第四赖氨酸三甲基化（histone 3 lysine 4 trimethylation，H3K4me3）和第九赖氨酸二甲基化（histone 3 lysine 9 dimethylation，H3K9me2）。通过实时 PCR 分析染色质重塑基因的表达和相关性。SHR 组织的 Ace1 表达高于 WKY 大鼠。两种品系的所有组织中 Ace1 启动子大多是非甲基化的。除了在肺部，SHR 组织的 Ace1 启动子区域富含 H3Ac 和 H3K4me3。SHR 的肾上腺、心脏和肾脏组织中 H3K9me2 的富集较少。缬沙坦治疗 SHR 降低了局部 Ace1 mRNA 和蛋白的表达，同时伴随着 H3K9me2 的增加，以及 H3Ac 和 H3K4me3 的减少。总之，通过组蛋白密码修饰，SHR 局部组织 ACE1 上调。
